This study identified a group of variables associated with each component of the PIRO staging system that are good predictors of hospital mortality for patients with CAS admitted to ICU.
Variables associated with response and organ-dysfunction took into account also their evolution over the first five days of ICU stay rather than as isolated measurements in each day. We summarize the dynamics of the measured variables with the initial value and how fast the variable changes over time (slope). These features seem to be more important than point-wise difference at specific days. This methodology was previously described concerning the same cohort of patients 
and it seems a suitable approach for the PIRO staging system. Interestingly, it is in accordance to what has been recently suggested as a more appropriate approach 
. It is worthwhile to highlight why this dynamic perspective may be more suitable when trying to stage sepsis patients; sepsis patients are not in a static condition but are markedly dynamic, as thus, changes overtime are much more informative of the clinical course than a single “picture” at the day of infection diagnosis or ICU admission. There are a number of variables that may not be available at the time of infection diagnosis or ICU admission but, when available, will change the treatment approach. Our perception of the patients is not determined only by the first evaluation but it changes over time with the clinical course and information coming from several diagnostic procedures (laboratory, radiology). Besides, to our knowledge, this is the first study to introduce biomarkers, namely CRP, as well as a dynamic approach to the PIRO staging system and we believe it may enhance its predictive accuracy concerning mortality, as the combination of the four PIRO's components presented very good discriminatory ability (AUC 0.85, CI95%
Moreover, we were able to confirm findings from previous studies concerning risk factors and procedures associated with an increase of mortality in sepsis patients: HCAS, higher severity of disease, fungal infections, positive blood cultures, MDR microorganisms and guideline non-concordant antibiotic therapy. Five prior studies, already mentioned, have been published addressing the PIRO concept: Moreno et al 
included variables from 2628 ICU sepsis patients in their model that were stratified into only three components, instead of the four original components of the PIRO system; this model showed fair ability to predict in-hospital mortality (AUC 0.77). Rubulotta et al 
used a regression tree analysis to create a PIRO score and obtained a limited discriminatory performance (AUC 0.70). Rello et al 
built a PIRO score from a cohort of 529 ICU patients admitted with community-acquired pneumonia. Their PIRO score showed very good discrimination (AUC 0.88) for known risks of community-acquired pneumonia. Lisboa et al 
created a PIRO score for 441 ICU patients with ventilator-associated pneumonia. The ventilator-associated pneumonia PIRO score had a very good discrimination (AUC 0.81). Howell et al 
built a derivation cohort to include 2132 patients to create a PIRO score. Their PIRO score also showed excellent discrimination (AUC 0.9). However, mortality in this cohort was very low as patients included came from the emergency department with “suspicion of infection” and patients with noninfectious diagnosis might also have been included.
We believe that our results show that the specific variables of each of the four domains are better suited than the variables from previous studies; in particular, we were able to select specific variables for each of the four components that may fit better to the consensus definition and concept of the PIRO.
All those previous studies present several limitations: restrict to a cohort of patients with a single cause of sepsis: community-acquired pneumonia or ventilator-associated pneumonia in the studies by Rello and Lisboa 
; based on secondary analysis of cohorts included on other studies with diverse aims as in the studies by Moreno and Rubollota 
; including patients with “suspicion of infection”, introducing the possibility that patients without sepsis might have been included, in particular if we look at the very low mortality rate in the study by Howell et al 
. However, those previous studies have added substantial information: we understood that the PIRO concept may be brought into practice and that the PIRO concept might improve future research of sepsis. In cancer research, patients are not categorized only with “cancer”, they are also categorized as having a tumor that might be T3N0M0. This categorization has practical implications for decisions such as initiating or not chemotherapy/radiotherapy or any new drug as well as the timing and type of surgery. In sepsis patients, we need to move forward and begin to try new therapies for patients presenting with different PIRO scores.
We believe that the novel aspects developed in our study, i.e., the inclusion of biomarkers for the R component and a dynamic view of the patient daily evolution are a step forward in the building of the PIRO staging system.
The limitations from the present study include those pointed out on previous studies with the same cohort of patients 
, namely the exclusion of nosocomial infections and the need for validation in an independent population. Concerning the R component we only assessed one biomarker, CRP. It is possible that other biomarkers, namely procalcitonin, or even assessing panels of biomarkers might improve the results. Moreover, for antibiotic therapy we used the definition of concordant antibiotic therapy 
as it was not possible to gather results according to adequacy of antibiotic therapy and microbiologic documentation was available in only 40% of the patients 
. In addition, definitions for cancer disease was restricted to the definition for metastatic cancer used in the original SAPS II study 
which may not reflect all the array of severity of cancer disease.
The present study has important strengths: it is the first step on trying to find a methodological way to describe a dynamic perspective on the PIRO staging system, with dynamic assessment of variables, an approach that may fit better to describe patients with sepsis as a dynamic process. Moreover, it is probably the first including more suitable variables for each of the four components of PIRO, in particular, the variables for the R component, which included the WCC and CRP in a dynamic view.
Currently, PIRO is still a research concept, not an established tool ready to be used at the bedside, however, with the present study we gave a step further in trying to find out which model with which variables may best fit on a tool able to give us, clinicians, information concerning the prognosis and treatment response of severe sepsis and septic shock and a step further on a future consensus. In conclusion, our results showed that this novel approach to PIRO concept present a good prediction of hospital mortality for patients with CAS admitted to ICUs. It is also our believe that PIRO system should be further investigated in order to become a true patient staging system with real treatment and prognostic implications in sepsis patients.